What are the dosing recommendations for apixaban (apixaban) in patients with impaired renal function?

Apixaban Dosing in Renal Impairment

Apixaban can be used across the spectrum of renal function with appropriate dose adjustments, and is the preferred direct oral anticoagulant in patients with severe renal impairment due to its lowest renal clearance (27%) among all DOACs. 1, 2

Standard Dosing by Renal Function

Normal to Mild Renal Impairment (CrCl >50 mL/min)

• Standard dose: 5 mg twice daily 1
• No dose adjustment required 1
• Renal function should be assessed at least annually 1

Moderate Renal Impairment (CrCl 30-50 mL/min)

• Standard dose: 5 mg twice daily 1
• Reduce to 2.5 mg twice daily if patient has ≥2 of the following:
  • Age ≥80 years
  • Body weight ≤60 kg
  • Serum creatinine ≥1.5 mg/dL 3, 1, 2

Severe Renal Impairment (CrCl 15-29 mL/min)

• Dose: 2.5 mg twice daily 1
• Apixaban is approved for use in this population, unlike other DOACs 1
• European guidelines support use with dose reduction in severe CKD 1

End-Stage Renal Disease on Hemodialysis (CrCl <15 mL/min)

• Dose: 5 mg twice daily 1
• Reduce to 2.5 mg twice daily if:
  • Age ≥80 years OR
  • Body weight ≤60 kg 1
• Apixaban is the only DOAC FDA-approved for ESRD on dialysis 4
• Systemic exposure increases 36% when dosed post-dialysis compared to normal renal function 2
• Dialysis clearance is approximately 18 mL/min, removing only 14% of drug during a 4-hour session 2

Critical Contraindications

Absolute contraindications based on renal function:

• CrCl <30 mL/min in cancer-associated VTE 3
• CrCl <25 mL/min per older NCCN guidelines 3
• CrCl <15 mL/min per initial FDA trials 3

Important caveat: While stage IV CKD (CrCl <30 mL/min) is not listed as an absolute contraindication in the FDA label, NCCN acknowledges insufficient data to support safe dosing in these patients, especially those on hemodialysis 3. However, more recent evidence and FDA approval now support use in ESRD with appropriate dosing 1, 4.

Pharmacokinetic Rationale

• Apixaban has 27% renal elimination, the lowest among all DOACs 3, 1, 2
• Primarily metabolized via CYP3A4 (73% non-renal clearance) 2
• Half-life approximately 12 hours 3, 2
• In ESRD patients, 2.5 mg twice daily produces exposure similar to standard dosing in patients with normal renal function 1
• The 5 mg twice daily dose produces supratherapeutic levels in chronic hemodialysis patients 1

Safety and Efficacy Evidence

Bleeding Risk

• Meta-analysis shows apixaban reduces major bleeding risk by 58% (OR 0.42) compared to warfarin in patients with renal impairment 5
• In ESRD patients on dialysis specifically, major bleeding risk reduced by 73% (OR 0.27) 4
• Pooled incidence of any bleeding on apixaban in advanced CKD/ESRD: 17.4% 4
• Apixaban appears safer than warfarin in severe renal impairment (9.6% vs 17.8% major bleeding, though not statistically significant) 6

Thromboembolic Events

• No significant difference in stroke or thromboembolism risk versus warfarin in ESRD (OR 0.56) 4
• Stroke rates similar between apixaban and warfarin (7.5% each) in severe renal impairment 6

Monitoring Requirements

• Calculate creatinine clearance using Cockcroft-Gault method 1
• Reassess renal function at least annually and when clinically indicated 1
• More frequent monitoring warranted in patients receiving nephrotoxic chemotherapy 3
• Monitor for signs of bleeding throughout therapy duration 7

Drug Interactions in Renal Impairment

• P-glycoprotein inhibitors increase apixaban concentrations 1
• Concomitant dual P-gp and strong CYP3A4 inducers/inhibitors may require dose adjustment or avoidance, particularly in CKD 1
• Apixaban is a substrate of P-gp and breast cancer resistance protein 2

Common Pitfalls to Avoid

1. Do not use rivaroxaban, dabigatran, or edoxaban in CrCl <30 mL/min - these have higher renal clearance and are contraindicated 3
2. Do not forget the dose reduction criteria - age ≥80 years, weight ≤60 kg, or creatinine ≥1.5 mg/dL (need ≥2 factors) 1, 2
3. Do not assume all DOACs are equivalent in renal disease - apixaban's 27% renal clearance makes it uniquely suitable 1
4. Do not overlook increased bleeding risk with GI/GU tract lesions - use with caution in these patients 3
5. In cancer patients, recognize limited data - most VTE trials excluded patients with CrCl <25-30 mL/min 3